Vortioxetine (Lu AA21004) in the long-term open-label treatment of major depressive disorder

Abstract

Objective:

The primary objective of this study was to evaluate the safety and tolerability of the investigational drug vortioxetine (Lu AA21004) in the long-term treatment of patients with major depressive disorder.

Methods:

Patients entered this 52-week, open-label extension study after completing an 8-week lead-in study. Safety and tolerability were evaluated at regular intervals on the basis of spontaneously reported adverse events (AEs), clinical safety laboratory tests, vital signs, ECG and physical examination. Effectiveness of treatment was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) total score.

Results:

A total of 535 patients were treated and 61.3% (n = 328) completed the study, resulting in 393 patient years of exposure to vortioxetine. AEs reported by ≥10% of patients were nausea, headache, and nasopharyngitis. Taken together, six patients had eight AEs related to sexual dysfunction. There were no clinically significant safety findings with respect to mean changes of vital signs, weight, ECG parameters, or clinical laboratory values. Patients entered the extension study with a mean MADRS total score of 13.5 ± 8.7. The mean MADRS total score decreased (improved) by approximately 8 points to 5.5 ± 6.0 at Week 52 (OC). By the end of the study, the proportion of responders had increased from 63% to 94% (OC), as had the proportion in remission (MADRS ≤10), increasing from 42% to 83% (OC). Patients in remission (n = 226) at the start of this study had a relapse rate (MADRS ≥22) of 9.7%.

Conclusions:

As with all open-label studies, the conclusions that can be drawn are limited by the lack of a placebo control, making it difficult to assess causality of any changes in outcome measures. However, on the basis of these findings, vortioxetine (2.5, 5, 10 mg/day) demonstrated a favourable safety and tolerability profile and maintained effectiveness over 12 months of treatment.

Trial Registration:

ClinicalTrials.gov identifier: NCT00694304.

Keywords::

• Effectiveness
• MADRS
• Multimodal
• Remission
• Response
• Tolerability
• Vortioxetine

Transparency

Declaration of funding

H. Lundbeck A/S sponsored the study as part of a joint development program with Takeda Pharmaceutical Company Limited. Lundbeck was involved in the study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

Authors D.S.B. and I.F. designed the original study, wrote the protocol and monitored study progress. T.H. undertook the statistical analysis. All authors contributed to and have approved the final manuscript.

Declaration of financial/other relationships

On behalf of his employer, D.S.B. received consulting fees for planning and supervising the study, and personal support for travel to study-related meetings. He has received honoraria for educational presentations from H. Lundbeck A/S, and has acted as a paid consultant to Eli Lilly, Lundbeck, Pfizer and Servier, and currently holds research grants (on behalf of his employer) from Lundbeck and Pfizer. He has accepted paid speaking engagements in industry-supported satellite symposia or other meetings hosted by GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer and Servier. T.H. and I.F. are employed by H. Lundbeck A/S.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgements

The authors would like to thank all patients for their participation in the study. The authors gratefully acknowledge the participation of the following investigators in the psychiatric sites in the trial: Australia: Richard Newton, Dhiren Singh, Mathew Samuel, Tom George, Saji Damodaran, Peter Farnbach; Bulgaria: Maria Alexandrova, Valentin Akabaliev, Emil Grashnov, Temenuzhka Mateva; Canada: Raymond Matte, Marie-Josée Filteau, Saibal Nandy, Paul Latimer, Meir Steiner, Richard Bergeron, David Bakish; Czech Republic: Erik Herman, Jiri Bilik, Michaela Klabusayova, Zdenek Solle, Slavomir Pietrucha, Olga Kratka; Estonia: Kaire Aadamsoo, Innar Tõru, Kadri Andresen; Finland: Jukka Penttinen, Marko Sorvaniemi, Marina Joffe, Anneli Timonen, Ulla Lepola; France: Mocrane Abbar, Christian Gaussares, Francis Gheysen, François-Xavier Poudat, Philippe Desbonnet, Patrick Singer, Daniel Bonnaffoux, Paule Khalifa, Christophe Dufour, Joël Pon, David Modavi, Marc Bonnard; Hong Kong: Ka Fai Chung; India: Venu Gopal Jhanwar, Rajesh Parikh, Lakshman Dutt, Vinay Barhale, Mahesh Chudgar; Republic of Korea: Hee Yeon Jung, Tae Youn Jun, Kang Seob Oh, Bum-Hee Yu, Jung Seo Yi; Latvia: Raisa Andrezina, Andris Arajs; Lithuania: Daiva Deltuviene, Marija Janulioniene, Rasa Jasaite, Valdone Matoniene, Dalia Peciukaitiene, Loreta Siaudvytyte; Malaysia: Abdul Kadir Abu Bakar, Esther G Ebenezer, Ahmad Hatim Sulaiman; the Philippines: Alma Jimenez, Beverly Azucena, Rodney Felimon Dalisay; Romania: Iosif Gabos Grecu, Elena Gherman, Lorentina Florescu, Cristian Gabriel, Marinescu, Maria Ladea, Camelia Mihaela Pantu, Maria Silvia Trandafir; the Slovak Republic: Maria Hastova, Nada Kuriackova, Juraj Mrazik; Spain: Juan Ignacio Franch, Celso Iglesias, Ángel Luis Montejo; Taiwan: Chieh-Liang Huang, Hsin-Chi Tsai/Chaucer CH Lin; Turkey: Aytekin Sır, Oğuz Karamustafalıoğlu, Tunç Alkın, Simavi Vahip; and the Ukraine: Yuliya Blazhevych, Svetlana Moroz, Iryna Vlokh, Volodymyr Abramov, Valeriy Bitenskyy, Natalya Maruta. The authors thank D.J. Simpson (H. Lundbeck A/S) for providing support in the preparation, revision, and editing of the manuscript.